Association between rs662 (A > G) and rs854560 (A > T) polymorphisms in PON1 gene and the susceptibility for psoriasis in mestizo population of Western Mexico.

Psoriasis is a chronic, autoimmune skin disease. In psoriasis, PON1 activity is diminished and peroxidation biomarkers are elevated. The most studied PON1 polymorphisms are rs662 (A > G) and rs854560 (A > T), which have been associated with the antioxidant activity of PON1, risk of cardiovascular diseases and psoriasis development. The aim of this study, was to determine the association of rs662 (A > G) and rs854560 (A > T) PON1 polymorphisms with psoriasis susceptibility in Western Mexico population. In this case-control study, we included 104 psoriasis patients and 124 control subjects. The genotyping of polymorphisms rs662 (A > G) and rs854560 (A > T) of PON1 was carried out by PCR-RFLPs. The lipid profiles were quantified by enzymatic colorimetric method, and PON1 activity was determined by spectrophotometry. The lipid profile levels, except HDL-C and atherogenic index, were higher in patients vs. controls. Patients presented lower paraoxonase and arylesterase activity. The G allele of rs662 (A > G) is associated with risk for psoriasis, while the T allele of rs854560 (A > T) is associated with low susceptibility to psoriasis. The AG haplotype was more frequent within the patient group (p < 0.05). The AA and AG genotypes of rs662 (A > G) and TT and AA genotypes of rs854560 (A > T) are associated with lower PONase and ARE activity in patients vs. controls. Patients with the G allele of rs662 (G > A) and T alleles of rs854560 (A > T) show significant differences in the lipid levels in comparison to controls. These results suggest that carriers of G allele of rs662 (A > G) present a greater susceptibility to psoriasis.

Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma.

BACKGROUND: Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival. METHODS: We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment. RESULTS: We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance. CONCLUSIONS: Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.

Antagonists of the stress and opioid systems restore the functional connectivity of the prefrontal cortex during alcohol withdrawal through divergent mechanisms.

Chronic alcohol consumption leads to dependence and withdrawal symptoms upon cessation, contributing to persistent use. However, the brain network mechanisms by which the brain orchestrates alcohol withdrawal and how these networks are affected by pharmacological treatments remain elusive. Recent work revealed that alcohol withdrawal produces a widespread increase in coordinated brain activity and a decrease in modularity of the whole-brain functional network using single-cell whole-brain imaging of immediate early genes. This decreased modularity and functional hyperconnectivity are hypothesized to be novel biomarkers of alcohol withdrawal in alcohol dependence, which could potentially be used to evaluate the efficacy of new medications for alcohol use disorder. However, there is no evidence that current FDA-approved medications or experimental treatments known to reduce alcohol drinking in animal models can normalize the changes in whole-brain functional connectivity. In this report, we tested the effect of R121919, a CRF1 antagonist, and naltrexone, an FDA-approved treatment for alcohol use disorder, on whole-brain functional connectivity using the cellular marker FOS combined with graph theory and advanced network analyses. Results show that both R121919 and naltrexone restored the functional connectivity of the prefrontal cortex during alcohol withdrawal, but through divergent mechanisms. Specifically, R121919 increased FOS activation in the prefrontal cortex, partially restored modularity, and normalized connectivity, particularly in CRF1-rich regions, including the prefrontal, pallidum, and extended amygdala circuits. On the other hand, naltrexone decreased FOS activation throughout the brain, decreased modularity, and increased connectivity overall except for the Mu opioid receptor-rich regions, including the thalamus. These results identify the brain networks underlying the pharmacological effects of R121919 and naltrexone and demonstrate that these drugs restored different aspects of functional connectivity of the prefrontal cortex, pallidum, amygdala, and thalamus during alcohol withdrawal. Notably, these effects were particularly prominent in CRF1- and Mu opioid receptors-rich regions highlighting the potential of whole-brain functional connectivity using FOS as a tool for identifying neuronal network mechanisms underlying the pharmacological effects of existing and new medications for alcohol use disorder.

Origin makes a difference: Alternative responses of an AM-dependent plant to mycorrhizal inoculum from invaded and native soils under abiotic stress.

The presence of invasive alien plants (IAPs) alters the composition of soil arbuscular mycorrhizal (AM) fungal communities. Although fundamental for plant development, plant responses to AM from invaded soils have not been widely explored, especially under environmental stress. We compared plant growth, P accumulation, root colonization and the photosynthetic responses of the native AM-dependent Plantago lanceolata growing in contact with AM fungi from communities invaded by Acacia dealbata Link (AMinv) or non-invaded communities (AMnat) exposed to water and light restriction (shade). Under optimal growing conditions, plants in contact with AMnat produced higher leaf biomass and accumulated more P. However, plant responses to different AM inocula varied as the level of stress increased. Inoculation with AMinv promoted plant growth and root length under light restriction. When plants grew in contact with AMnat under drought, leaf P increased under severe water restriction, and leaf and root P increased under intermediate water irrigation. Growing in contact with the AMnat inoculum promoted root P content in both full light and light restriction. Colonization rates of P. lanceolata roots were comparable between treatments, and plants maintained photosynthetic activity within similar ranges, regardless of the level of stress applied. Our results suggest that origin of the inoculum (native soils versus invaded soils) did not affect the ability of AM species therein to establish effective mutualistic associations with P. lanceolata roots but did influence plant responses depending on the type and level of the abiotic stress.

Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2.

Proteins encoded by the fringe family of genes are required to modulate Notch signalling in a wide range of developmental contexts. Using a cell co-culture assay, we find that mammalian Lunatic fringe (Lfng) inhibits Jagged1-mediated signalling and potentiates Delta1-mediated signalling through Notch1. Lfng localizes to the Golgi, and Lfng-dependent modulation of Notch signalling requires both expression of Lfng in the Notch-responsive cell and the Notch extracellular domain. Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1-expressing cells. Lfng potentiates both Jagged1- and Delta1-mediated signalling via Notch2, in contrast to its actions with Notch1. Our data suggest that Fringe-dependent differential modulation of the interaction of Delta/Serrate/Lag2 (DSL) ligands with their Notch receptors is likely to have a significant role in the combinatorial repertoire of Notch signalling in mammals.

Sequential blinded treatment decisions in ALK-positive non-small cell lung cancers in the era of precision medicine.

Next-generation ALK TKIs have become the new standard of care in first-line setting in advanced ALK-positive NSCLC patients. However, sequential strategies at progression are relevant, as may have an impact on patients' outcome. In this commentary we discuss whether genomic-tailored strategies at progression would be more suitable for improving outcome of ALK-positive NSCLC patients.

A dual embryonic origin for vertebrate mechanoreceptors.

Neuromasts, the mechanoreceptors of the lateral line system of fishes and aquatic amphibians, have previously been thought to develop exclusively from embryonic epidermal placodes. Use of fate mapping techniques shows that neuromasts of the head and body of zebrafish, Siamese fighting fish, and Xenopus are also derived from neural crest. Neural crest migrates away from the neural tube in developing vertebrates to form much of the peripheral nervous system, pigment cells, and skeletal elements of the head. The data presented here demonstrate that neuromasts are derived from both neural crest and epidermal placodes.

Interactions of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration.

BACKGROUND: In the trunk of avian embryos, neural crest migration through the somites is segmental, with neural crest cells entering the rostral half of each somitic sclerotome but avoiding the caudal half. Little is known about the molecular nature of the cues-intrinsic to the somites-that are responsible for this segmental migration of neural crest cells. RESULTS: We demonstrate that Eph-related receptor tyrosine kinases and their ligands are essential for the segmental migration of avian trunk neural crest cells through the somites. EphB3 localizes to the rostral half-sclerotome, including the neural crest, and the ligand ephrin-B1 has a complementary pattern of expression in the caudal half-sclerotome. To test the functional significance of this striking asymmetry, soluble ligand ephrin-B1 was added to interfere with receptor function in either whole trunk explants or neural crest cells cultured on alternating stripes of ephrin-B1 versus fibronection. Neural crest cells in vitro avoided migrating on lanes of immobilized ephrin-B1; the addition of soluble ephrin-B1 blocked this inhibition. Similarly, in whole trunk explants, the metameric pattern of neural crest migration was disrupted by addition of soluble ephrin-B1, allowing entry of neural crest cells into caudal portions of the sclerotome. CONCLUSIONS: Both in vivo and in vitro, the addition of soluble ephrin-B1 results in a loss of the metameric migratory pattern and a disorganization of neural crest cell movement. These results demonstrate that Eph-family receptor tyrosine kinases and their transmembrane ligands are involved in interactions between neural crest and sclerotomal cells, mediating an inhibitory activity necessary to constrain neural precursors to specific territories in the developing nervous system.

Prevalence of pain and relative diagnostic performance of screening tools for neuropathic pain in cancer patients: A cross-sectional study.

BACKGROUND: Neuropathic pain can be overlooked in cancer patients. The advent of screening tools can help in recognizing it. However, little is known about their relative diagnostic performance and factors that affect it. This study evaluated the prevalence of neuropathic pain using several diagnostic strategies in cancer patients undergoing chemotherapy. METHODS: Patients attending the Oncology Unit of the investigators' site to continue their chemotherapy schedule were systematically screened for this cross-sectional study. Before starting chemotherapy drugs, pain specialists made a clinical diagnosis of neuropathic pain (either disease related, treatment related or comorbid) and medical oncologists administered three validated screening tools. Their relative diagnostic performance and the impact of some pain features on it were analysed using multivariate statistical methods. RESULTS: From a total of 358 patients, 194 (54.2%) suffered from pain and 73 (20.4%) had a clinical diagnosis of pure neuropathic or mixed pain. Among the screening tools, the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) was more specific (93.4%), although less sensitive (68.1%) than the Douleur Neuropathique in 4 Questions (DN4) (sensitivity: 87.5%, specificity: 88.4%). Interestingly, the specificities of these two instruments did not differ in patients with mild pain, while the DN4 remained to be more sensitive than the LANSS regardless of pain severity. CONCLUSIONS: Neuropathic pain is common in cancer patients undergoing chemotherapy. The DN4 might be of great help for the early detection of patients at risk because of incipient chemotherapy-related neuropathies and the LANSS to rule out neuropathic pain in patients with complex pain conditions.

The ecological cost of morphological specialization: feeding by a fossorial lizard.

Head size and shape of reptiles may reflect selection for multiple uses. For example, sexual selection for large head size may enhance feeding efficiency. In contrast, morphological characteristics of the heads of fossorial reptiles suggests that fossoriality may have evolved at the expense of reduced effectiveness in feeding. Our research focused on the question: Does a fossorial lizard feed less effectively than a non-fossorial lizard? To answer this question, we measured the time, number of bites, and oxygen consumption by sand-swimming (Chalcides ocellatus) and epigeal (Eumeces inexpectatus) skinks feeding on crickets. These lizard species were similar in mass, but different in body form: Chalcides had longer bodies and smaller heads than Eumeces. For lizards of the same mass, Chalcides were unable to eat prey as large as those eaten by Eumeces, Chalcides took longer to eat prey of the same size than did Eumeces, and the aerobic energy cost of eating crickets of the same relative size (cricket mass/lizard mass) tended to be greater for Chalcides than for Eumeces. The ecologically relevant costs of feeding appear to be the upper limit to the size of prey and the time of feeding. Both costs would restrict the energy intake per unit time of Chalcides. Moreover, given the same energy requirements and prey community, Chalcides would have to feed more often and would take longer to feed than would Eumeces. Both factors would increase the exposure of Chalcides to predators relative to that of Eumeces. To reduce the risk of predation, Chalcides would have to reduce energy intake or fulfill its energy requirements with relatively small prey, or both. These conclusions are potentially confounded in two ways. The first is that male Eumeces have relatively large heads as a result of sexual selection. Thus, the differences we observed between Chalcides and Eumeces (most of our specimens were males) could have been the result of reduced costs of feeding for Eumeces due to sexual selection and not the result of enhanced costs of feeding for Chalcides. A more likely explanation is that differences in the costs of feeding observed between these species reflect adaptations for fossoriality by Chalcides and sexual selection on Eumeces. Our results may also be confounded because we compared laboratory reared Chalcides with field captured Eumeces. Any deterimental effects of captivity on the vigor of Chalcides would increase their costs of feeding relative to those of Eumeces. Although short-term captivity is not associated with changes in the metabolic capcity of lizards, effects of long-term captivitiy are unknown.

Hypochord, an enigmatic embryonic structure: study of the axolotl embryo.

The hypochord of the axolotl embryo is first visible at an early tailbud stage, forming a rod-like structure, situated immediately under the notochord. A profusion of extracellular matrix fibrils is attached to the dorsolateral regions of the hypochord, linking it with the somites. A basal lamina develops around the hypochord, indicating an epithelial type of cell differentiation. Abundant rough endoplasmic reticula in the hypochord cells suggest lively synthetic activity. Prospective endoderm cells were vitally labeled with the lipophilic dye 1,1-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD) at the gastrula stage. Cells labeled with the dye were later found in the hypochord as well as in the gut endoderm. This shows that the hypochord is of endodermal origin, contrary to recent suggestions that the hypochord is of mesodermal origin, but consistent with histological data. After about 8 days of existence, the hypochord disappears. Experimental results, using an apoptosis detection kit, indicate that the hypochord cells may disintegrate by a type of apoptotic cell death. The close association between the hypochord and developing dorsal aorta suggests that the hypochord could be involved in the positioning of the dorsal aorta, which forms under it.

Deposition of atmospheric nitrogen compounds in humid tropical Cuba.

Acid deposition, a direct effect of gaseous air pollutants, is causing widespread damage to terrestrial and aquatic ecosystems. Further, these pollutants are responsible for the corrosion of building materials and cultural objects, as well as having an impact on human health. In Cuba, main atmospheric deposition of nitrogen compounds varies from approximately 12.0 to 65.0 kg N ha(-1) year(-1) in rural areas. Ammonia and ammonium are the most important elements in Cuba's tropical conditions.

[Biodistribution of 99mTC-HMPAO in healthy rats and B16 melanoma carriers]. / Biodistribución de 99mTc-HMPAO en ratones sanos y portadores de melanoma B16.

Scintigraphic studies carried out in melanoma patients have demonstrated that the 99mTc-HMPAO complex makes it possible to locate the lesion. A biodistribution and pharmacokinetic study of the 99mTc-HMPAO complex was carried out in B16-melanoma tumor healthy and carrier mice after an intravenous injection. Radioactivity was measured in the liver, kidneys, spleen, stomach, brain, blood and tumor. It was seen that at 15 minutes of the injections, 40% of the total activity distributed in the animal body was recorded in the tumor. An interesting effect observed is an increase in the tissue distribution curves in both experimental groups at 1-2 hours post-injection. According to the seriated imaging study results with 99mTc-HMPAO in B16 melanoma bearing mice, the best image is obtained 10-30 minutes after the injection.

The corrosion of nickel-titanium rotary endodontic instruments in sodium hypochlorite.

AIM: To evaluate the corrosion resistance of nickel-titanium (NiTi) endodontic rotary instruments immersed in 5.25% sodium hypochlorite (NaOCl) solution. METHODOLOGY: The corrosion performance of NiTi instruments (S1 25 mm, ProTaper Dentsplay Maillefer, Ballaigues, Switzerland) was evaluated using commercial 5.25% NaOCl solution (pH = 12.3), and the same solution partially neutralized adding H2SO4 to reach pH = 10.1. Electrochemical measurements were carried out using a potentiostat equipped with a five-channel zero resistance ammeter (ZRA) for galvanic current measurements. The instruments were sectioned into three parts (cutting part, noncutting part and shank) and degreased with acetone and rinsing with demineralized water prior to being immersed in NaOCl solution for testing. Each set of the three parts constituted one 'virtual' instrument through the ZRA, giving access to the galvanic currents that circulate between the three parts. Nine instruments were employed to check the reproducibility of the electrochemical measurements. RESULTS: The corrosion potential (E(corr)) of the NiTi alloy reached the passive domain in approximately 20 s of immersion in the solution having a pH 10.1. After this initial period the potential remained steady, indicating that stable passivation was achieved. However, at pH 12.3 no stationary state was achieved even after 6000 s of immersion time. Thus, the alloy was not stable in this medium from a corrosion point of view. CONCLUSIONS: The corrosion resistance of NiTi alloy was enhanced by lowering the pH of NaOCl solution to 10.1, which allows the system to reach the stability domain of the passivating species TiO2 and NiO2.